RESUMEN
The hydrindane (bicyclo[4.3.0]nonane) structural motif (1) and related cis-1-hydrindanone skeleton (2) are common substructures in many natural products. Herein, we describe efficient access to substituted cis-1-hydrindanones enabled by a sequence of Michael reactions. A copper-catalyzed intermolecular Michael addition of a cyclic silyl ketene acetal to a ß-substituted-α-alkoxycarbonyl-cyclopentenone enables construction of a quaternary center and is followed, after incorporation of an additional Michael acceptor, by a second, intramolecular addition of a nucleophilic ß-ketoester. This strategy affords stereoselective access to substituted bicyclic cis-hydrindanone ring systems containing up to three contiguous stereocenters.
RESUMEN
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT), is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.
Asunto(s)
NAD/metabolismo , Plasmodium falciparum/metabolismo , Transporte Biológico , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Humanos , Metabolómica , Nicotinamida-Nucleótido Adenililtransferasa/antagonistas & inhibidores , Nicotinamida-Nucleótido Adenililtransferasa/metabolismo , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Plasmodium falciparum/crecimiento & desarrolloRESUMEN
An efficient four-step synthesis of PA-824, a promising antituberculosis drug candidate, has been developed. This concise approach offers significant improvements over the synthetic route currently used for large-scale production.
Asunto(s)
Antituberculosos/síntesis química , Nitroimidazoles/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Hidrólisis , Cinética , Nitroimidazoles/química , Nitroimidazoles/farmacología , EstereoisomerismoRESUMEN
A di-O-TBS protected glyceraldehyde synthon was condensed with Ellman's reagent to form a bench-stable N-tert-butanesulfinyl imine 6, which served as a common intermediate for the stereoselective introduction of various R groups. The Ellman adducts were converted to useful multifunctional intermediates 18a-i in one pot. The alcohols 18a-i were efficiently elaborated to both known and novel anti-N-protected-3-amino-1,2-epoxides in two steps. Compound 2a is a key intermediate toward HIV protease inhibitors.
Asunto(s)
Compuestos Epoxi/química , Compuestos Epoxi/síntesis química , Gliceraldehído/química , Nitrógeno/química , Compuestos de Sulfonio/química , Aminoácidos/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Línea Celular Tumoral , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CHO , Permeabilidad Capilar/efectos de los fármacos , Chlorocebus aethiops , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Cristalografía por Rayos X , Entropía , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformación Molecular , Pleuresia/tratamiento farmacológico , Conejos , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] New air-stable PdCl(2){P(t)Bu(2)(p-R-Ph)}(2) (R = H, NMe(2), CF(3),) complexes represent simple, general, and efficient catalysts for the Suzuki-Miyaura cross-coupling reactions of aryl halides including five-membered heteroaryl halides and heteroatom-substituted six-membered heteroaryl chlorides with a diverse range of arylboronic acids. High product yields (89-99% isolated yields) and turn-over-numbers (10,000 TON) are observed.
RESUMEN
[reaction: see text] CuI-catalyzed N-arylation of imidazoles with aryl bromides has been achieved in a near-homogeneous system that utilizes tetraethylammonium carbonate as base, 8-hydroxyquinoline as ligand, and H2O as cosolvent. Preliminary results with aryl chlorides are also reported.
Asunto(s)
Cobre/química , Hidrocarburos Halogenados/química , Imidazoles/síntesis química , Alquilación , Catálisis , Imidazoles/química , Estructura Molecular , Solubilidad , EstereoisomerismoRESUMEN
A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.
Asunto(s)
Imidazoles/síntesis química , Integrina alfaVbeta3/antagonistas & inhibidores , Naftiridinas/síntesis química , beta-Alanina/análogos & derivados , Catálisis , Ciclización , Estructura Molecular , Estereoisomerismo , beta-Alanina/síntesis químicaRESUMEN
The Sharpless asymmetric dihydroxylation reaction of enol ethers derived from their corresponding cyclic ketones, gave alpha-hydroxyketones with high enantioselectivity. The enantiomeric excess was found to be proportional to the length of the unbranched enol ether chain with a maximum ee for the pentyl enol ether. An efficient synthesis of alpha-hydroxy chromanone in >90% ee was demonstrated using this method.
RESUMEN
A convergent synthesis was developed for the production of the core structure of prostaglandin D(2) receptor antagonists for the treatment of allergic rhinitis. The key steps in this synthesis were a highly diastereoselective alkylation of (+)-nopinone, a chemo- and stereoselective reduction of an oxime to an amine, and a well-controlled reduction of an aminoalkyne to a (Z)-olefin.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/síntesis química , Técnicas Químicas Combinatorias , Receptores Inmunológicos , Receptores de Prostaglandina/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Alquilación , Cicloparafinas/síntesis química , Resonancia Magnética Nuclear Biomolecular , Oxidación-Reducción , Estereoisomerismo , TemperaturaRESUMEN
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
Asunto(s)
Morfolinas/síntesis química , Antagonistas del Receptor de Neuroquinina-1 , Aprepitant , Cristalografía por Rayos X , Lactamas/síntesis química , Lactamas/química , Estructura Molecular , Morfolinas/química , Oxazinas/química , EstereoisomerismoRESUMEN
[reaction: see text] The relative and absolute configuration of the pneumocandin B(0) side chain has been established as (10R,12S)-dimethylmyristoyl by the stereocontrolled synthesis of both antipodes of the side chain acid and their comparison to a sample derived from the natural product.
Asunto(s)
Antibacterianos/química , Antibacterianos/síntesis química , Antifúngicos/química , Antifúngicos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Péptidos , Equinocandinas , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura MolecularRESUMEN
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
RESUMEN
An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.
Asunto(s)
Ciclopentanos/química , Ciclopentanos/síntesis química , Ciclopropanos/química , Ciclopropanos/síntesis química , Indicadores y Reactivos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Ciclohexanos/síntesis química , Ciclopentanos/síntesis química , Sustancia P/antagonistas & inhibidores , Catálisis , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
An efficient synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio containing side chain of ertapenem (MK-0826) is described. Starting material N-(O,O-diisopropyl phosphoryl)-trans-4-hydroxy-L-proline is converted in a one-pot process to (2S)-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid monohydrochloride in 70-75% overall yield via a series of six reactions. The development of each of these reactions and the isolation of the product is discussed in detail.
Asunto(s)
Antibacterianos/síntesis química , Antiinfecciosos/síntesis química , Carbapenémicos/síntesis química , Técnicas Químicas Combinatorias , Lactamas , Antibacterianos/química , Antiinfecciosos/química , Carbapenémicos/química , Cromatografía Líquida de Alta Presión , Ertapenem , Estructura Molecular , Pirrolidinas/química , Estereoisomerismo , beta-LactamasRESUMEN
3-Pyridylboronic acid was prepared in high yield and bulk quantity from 3-bromopyridine via a protocol of lithium-halogen exchange and "in situ quench". This technique was further studied and evaluated on other aryl halides in the preparation of arylboronic acids.
RESUMEN
[reaction: see text] The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-delta-lactones in a two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones.
Asunto(s)
Efedrina/química , Catálisis , Cristalografía por Rayos X , Indicadores y Reactivos , Lactonas/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , EstereoisomerismoRESUMEN
Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.